Demand the impossible
What is gene therapy capable of today
Anton Soldatov, TASS
30 years ago, for the first time, a person was cured of a deadly disease by gene therapy. Then many were waiting for a breakthrough, but the mass introduction of this technology has not yet happened. Only a few drugs received approval, and their price turned out to be sky-high. How did it happen and what is happening with the gene therapy of hereditary diseases now?
Deputy Prime Minister Tatyana Golikova announced the creation of a fund for the treatment of children with spinal muscular atrophy (SMA), which will receive additional tax fees. SMA is one of the most frequent causes of infant mortality caused by hereditary diseases. And one of the few such diseases that can be radically treated. SMA occurs due to a mutation in the gene that ensures the functioning of motor neurons. In severe form, the muscles gradually weaken to such an extent that a person cannot swallow and breathe. In Russia, more than 2 thousand people have this diagnosis, and only 8% of patients live more than two years.
Last year, the drug Zolgensma was approved in the USA – it introduces a healthy copy of the gene into the patient's cells, which makes up for the lack of an important protein. Only one injection is needed, but its cost exceeds $ 2 million. But children who receive it early enough get a chance for an almost complete recovery. Now the drug is undergoing the registration procedure in Russia, but in the future it may become the drug of choice – that is, the one that doctors prescribe in the first place.
Zolgensma is an example of unambiguous success of gene therapy. But over the past 30 years, the technology itself has managed to survive both a surge of interest and disappointment, which almost buried its prospects.
The girl who survived
Ashanti de Silva is a smiling young woman with curly hair who holds herself loosely in front of the camera. It's hard to believe, but once her health was more fragile than that of a 90-year-old old woman. At the age of two, Ashanti was diagnosed with severe combined immunodeficiency (TCID). The reason was a congenital "breakdown" in a gene that plays a key role in the creation of lymphocytes – immune cells.
Without specific treatment, most patients with TCD die in the first year of life. The only chance for recovery until recently was a bone marrow transplant. But for this it was necessary to find a compatible donor, and this is possible only in 10-20% of cases. In the rest, minimal body protection was maintained with gamma globulin injections. But such children were still weak and doomed to isolation from the world.
A sad example is David Vetter, whom journalists dubbed "the boy in the bubble." His parents found out about the disease before he was born, but hoped for a transplant from a healthy daughter. However, the tests showed incompatibility, and in the hope of medical progress, the boy was temporarily placed in a sterile plastic bubble. The wait dragged on for 12 years. When the doctors did manage to do the transplant, it turned out that a virus was hiding in the transplant – it killed the boy.
Ashanti was three times unlucky: a few months after the start of drug therapy, her body lost sensitivity to her, and a compatible donor could not be found. But in one thing, her luck still smiled. It drew the attention of geneticist William Anderson, who was just experimenting with the delivery of genetic material to cells using viruses. By that time, he had already successfully tested the technology on animals and humans, and now he was looking for volunteers for a more breakthrough study.
Ashanti's parents agreed. Anderson took the defective cells from her blood, implanted a working copy of the gene into them, then multiplied them in a test tube to the required amount and injected them back into the bloodstream. The results were stunning: six months later, the number of healthy white cells in the girl's body rose to normal levels. However, the recovery was not complete – the treatment courses had to be repeated regularly. But Ashanti was able to live a normal life.
Work on bugs
Anderson's success sparked a wave of interest in the new treatment method. Time magazine put him on a par with Hippocrates and Pasteur. But soon the enthusiasm was replaced by disappointment. 300 trials were conducted involving thousands of patients with dozens of diseases – from brain tumors to cystic fibrosis and hereditary heart disease – but the results were more than modest. Only a few people had significant improvement. In 1999, one of the patients died. The investigation revealed hundreds of cases of complications in other experiments, and the reputation of gene therapy was undermined for years.
Most of the early failures were due to the unpredictable behavior of viruses. On the one hand, they were and remain ideal gene editing tools. For millions of years, viruses have honed their ability to infiltrate other people's cells and change their "program" in order to survive. On the other hand, the body of patients could not always distinguish the therapeutic virus (vector) from the usual causative agent of infection. The death of the patient in 1999 was caused precisely by an immune reaction, which was provoked by the injected virus.
Another problem emerged three years later, in another study involving 11 children with TKID (they also could not find a donor). The treatment showed results in nine, but a few years later four of them fell ill with leukemia. This happened because the carrier virus accidentally disrupted the work of genes that provoke malignant cell degeneration. Although cancer in all children was defeated by chemotherapy, one of them still died during the repeated administration of the drug.
Interestingly, the parents themselves asked the scientists to continue the treatment. They understood that there was simply no other chance. Therefore, even serious "side effects" did not lead to a refusal to study the possibilities of gene therapy. Regulatory agencies have tightened monitoring of trials, increased the number of inspections and created a new system for reporting serious side effects. At the same time, funding for programs continued, and the development of new therapies moved from universities to private companies.
The researchers focused their efforts on creating more efficient and safe vectors for the delivery of genetic material (including non-viral ones). Already in 2009, an article was published in the scientific journal Nature, in which the authors praised the scrupulousness of scientists, calling on the scientific community to give technology a "new chance". And in 2012, the European Medical Agency approved the first gene therapy drug for commercial use.
The price of victory over nature
The drug Glybera from the biotech company UniQure and the Italian pharmaceutical company Chiesi was intended for the treatment of lipoprotein lipase deficiency syndrome. With this disease, the breakdown of fats in the digestive tract is disrupted, and the frequency of its occurrence is quite low – one case per million people. Although the syndrome is not fatal, it requires adherence to a strict fat-free diet and can cause attacks of severe pancreatitis. Patients are also not recommended to have children.
Although the approval of Glybera was presented in the press as a breakthrough, the sales results turned out to be negligible: only one buyer was found in five years. There were several reasons. Firstly, in most of the study participants, therapy only relieved the symptoms, but did not remove them at all. Moreover, for many, the effect decreased over time, and it was impossible to re-inject the drug: the body had time to study the virus and develop protection against it. Secondly, the drug turned out to be fabulously expensive – $ 1 million per injection. As a result, it was withdrawn from sale.
In 2016, the Strimvelis drug was approved in Europe for the treatment of the same combined immunodeficiency. This time, the problems with the risk of developing blood cancer were solved, since a safer gamma retrovirus was used for delivery. However, in two years only five patients received the drug. The reasons are the same – most simply could not afford treatment for €594,000.
Another drug, Luxturna, entered the American market in 2018, and in 2019 it was approved in Europe. It was intended to treat a hereditary form of early blindness. According to statistics, only in the USA from 1000 to 2000 people suffer from it. The test results were not perfect: in only half of the patients, the drug showed a significant effect. At the same time, it worked better on those who had a more moderate drop in vision. The cost of an injection into both eyes costs $ 800 thousand. But in the first half of 2019, more than 15 ampoules of Luxturna were sold in the USA alone. It was a relatively good result.
Finally, in 2019, the American FDA regulator approved the drug Zolgensma for the treatment of spinal muscular atrophy. It is too early to talk about a complete cure with the help of Zolgensma. But studies have shown that 19 out of 36 patients two years after using the drug could sit without support, whereas without therapy only half of them would have survived, and no one would have been able to sit.
And yet, why is it so expensive?
The high price remains the main difficulty for the widespread use of gene therapy – as well as the continuation of developments in this direction. The cost of any medicine includes the costs of its creation, testing and advertising. Before receiving approval, the trials go through four phases – preclinical (in animals) and three clinical (in humans). At least ten people are needed for the first clinical phase. At the same time, the test on only one participant can cost up to $ 1 million. According to Novartis, which produces Zolgensma, the total cost of developing the drug exceeded $ 1 billion.
Medicines "for everyone" are naturally cheaper, because millions of people will buy them. In the treatment of rare diseases, the circle of consumers is by definition very small. To date, from 5 to 8 thousand rare hereditary diseases have been identified in the world. Many of them have several forms, and not all are well studied. For example, the same TKID may be associated with a disorder in the ADA gene (as in Ashanti de Silva) or in the IL2RG gene (as in David Vetter). In each case, the specific mechanism of gene introduction will be different – it depends on its location, expression (work) in different tissues, influence on other processes in the body.
To determine a fair price, pharmacoeconomists resort to conditional indicators, for example, the patient's quality of life, taking into account the years lived (QALY). One QALY is equal to one year of healthy life. In the USA, it is estimated at about $ 150 thousand. A drug that prolongs life by a year, but worsens its quality by half (for example, due to the need to be in a hospital ward all the time) has 0.5 QALY. So, the treatment should not be more expensive than $ 75 thousand.
For gene therapy drugs, the QALY index can be huge simply because there are no analogues or they give only a temporary effect. For example, for Zolgensma, the index is 15.9, and for another drug from SMA Spinraza – only 5.3. At the same time, Spinraza must be taken every year so that the effect persists. With this in mind, the costs are even higher (more than $ 500 thousand per one-year course).
But in the case of gene therapy, even these estimates still have to be taken on faith. There are no studies that would track the condition of treated patients for at least ten years. And we know that hooked genes can behave unpredictably. In addition, a sample of three dozen patients will not show a sufficiently wide range of adverse reactions.
We should expect an explosion
Currently, more than 900 new drugs for gene therapy are under consideration only by the American Agency for Drug Safety Control (FDA). But this does not mean that all of them will be approved. The agency has very strict criteria. For example, an application for one of the most anticipated drugs of recent times – a remedy for hemophilia Roctavian – was rejected in August of this year. Although it showed good results in the short term, it was not possible to prove the stability of the effect.
According to the number of approved drugs, it is impossible to judge the state of progress in the field as a whole, according to the scientific director of the Institute of Human Stem Cells Roman Deev. "Regulators more often act on the principle of "it is better to prohibit than to allow," he explains. "With such a careful approach, the drug may be in development for decades." In addition, research in the field of cancer therapy and viral diseases is more cost-effective, they make up the majority of applications for clinical trials.
The chances of cheaper and faster development are associated with new technologies – for example, CRISPR / Cas9, which is also called molecular scissors. It is also based on the "plagiarism" of other people's abilities – only not viral, but bacterial. This is an immune mechanism that some bacteria (such as streptococci) use to cut the genomes of attacking pathogens and destroy them. For the discovery of this method, they even awarded the Nobel Prize in Chemistry in 2020. Editing with CRISPR/Cas9 is cheaper than other methods.
Already, experiments in this direction show good results against such a disease as sickle cell anemia. It makes red blood cells wrinkled and brittle (hence the name), which is why they do not tolerate oxygen well. A person constantly feels tired, suffers from edema, ulcers on the legs, blockage of blood vessels. In a 2019 study by scientists using CRISPR/Cas9 managed to almost completely renew blood cells in a 33-year-old woman by making an incision in one gene.
According to Pavel Gershovich, Director of the Department for the development of gene therapy drugs at BIOCAD, in the coming years we can expect the growth of genomic editing technologies, primarily for the treatment of hereditary diseases. According to the forecasts of the same FDA, by the mid-2020s, 10-20 gene therapy drugs per year will receive registration. Russia has its own developments – for example, clinical trials of the first phase of a hemophilia drug will start next year.
In addition, over time, treatment with gene therapy drugs will become more accessible. Even now, a computer can predict how genes will work in a living cell if its state changes. The use of such methods will help to abandon expensive experiments, replacing them with modeling. After all, the first genetic tests once cost more than $1,000. And now they can be ordered for just $100.
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